The invention relates to a method for ameliorating inflammation of the gastrointestinal tract, such as that associated with inflammatory bowel disease, in a subject. The method involves administering a nucleic acid comprising an immunomodulatory nucleotide sequence to the subject. The immunomodulatory sequence can be administered alone or together with an additional therapeutic agents.
Gastrointestinal inflammation is one of the most common types of inflammatory process which affects humans (for a review, see, e.g., Bamford, FEMS Immunol Med Microbiol (1999) 24(2):161-8). Inflammatory bowel disease (IBD), a form of chronic gastrointestinal inflammation, includes a group of chronic inflammatory disorders of generally unknown etiology, e.g., ulcerative colitis (UC) and Crohn""s disease (CD). Clinical and experimental evidence suggest that the pathogenesis of IBD is multifactorial involving susceptibility genes and environmental factors (Sartor Am J Gastroenterol. (1997) 92:5S-11S). The interaction of these factors with the immune system leads to intestinal inflammation and dysregulated mucosal immunity against commensal bacteria, various microbial products (e.g., LPS) or antigens (Mayer et al. Current concept of IBD: Etiology and pathogenesis. In xe2x80x9cInflammatory Bowel Diseasexe2x80x9d 5th edition 2000, Kirsner J B editor. W. B. Sanunders Company, pp 280-296; for a discussion of IBD in children see, e.g., Walker-Smith, Postgrad Med J (2000) 76(898):469-72).
Human Crohn""s disease (CD) is thought to be characterized by type 1 Helper T (Th-1) response, which produce the cytokines interleukin IL-2, interferon xcex3, and tumor necrosis factor TNF (for a review of anti-TNFxcex1 therapy in Crohn""s disease, see, e.g., Mikula Gastroenterol Nurs. (1999) 22(6):245-8; Selby, Vet Microbiol (2000) 77(3-4): 505-511). Ulcerative colitis (UC) is dominated by type 2 Helper T (Th-2) response which produce anti-inflammatory cytokines such as IL-4, IL-5 and IL-10. However, the demarcation between Th-1 and Th-2 response in CD and UC is not an xe2x80x9call or nonexe2x80x9d response and it seems that there is significant overlap.
Animal models of colitis have highlighted the prominent role of CD4+T cells in the regulation of intestinal inflammation (Blumberg et al. Curr Opin Immunol (1999) 6:648-56). Cytokine imbalance, and the production of inflammatory mediators have been postulated to play an important role in the pathogenesis of both experimental colitis and IBD (Papadakis et al. Annu Rev Med (2000) 51:289-98; for a review, see, e.g., Blumberg JAMA (2001) 285(5):643-647; Nagura et al. Digestion (2001) 63 Suppl S1:12-21). In particular, dysregulated CD4+T cell responses play a pivotal role in the pathogenesis of experimental colitis (Bhan et al. Immunol Rev (1999) 169:195-207). Indeed, Th1 cytokines (e.g., IL-12) are dominant in inflamed mucosa of CD, whereas Th2 cytokines (e.g., IL-4) are relatively common in UC. In this respect, dinitrobenzene sulphonic acid-induced colitis (DNB), which is characterized by predominating Th1 response in mice (Neurath et al. Int Rev Immunol (2000) 19:51-6) mimics CD, whereas dextran sodium sulphate (DSS) induces acute and chronic colitis with a mixed Th1/Th2-like response, features UC (Dieleman et al. Clin Exp Immunol (1998) 114:385-91). Studies using transgenic mice having deletions in a cytokine gene develop a spontaneous inflammatory bowel disease (for a review see, e.g., MacDonald, Eur J Gastroenterol Hepatol (1997) 9(11):1051-50). animals having cytokine DNB-induced colitis, which is driven by mucosal Th1 response, has been reported to be accelerated by rIL-12 and inhibited by administration of anti-IL-12 antibodies (Neurtah et al. (2000), ibid). The inflammatory process and the immune response at mucosal sites result in mucosal barrier dysfunction leading to further exposure to enteric bacteria and/or their products that perpetuate mucosal inflammation (Podolsky Am J Physiol (1999) 277:G495-9).
Immunosuppressive and anti-inflammatory agents in high maintenance doses are the principal drugs used in the therapy of chronic inflammatory gastrointestinal disorders. Anti-inflammatory drugs presently used in treatment of IBD include aminosalycilates and immunosuppressive agents such as corticosteroids, azathioprine, cyclosporine and methotrexate. Corticosteroids remain the mainstay of anti-inflammatory and immunosuppressive therapy for many gastrointestinal conditions (see, e.g., Hyams, Curr Opin Pediatr (2000);12(5):451-5). Recently, specific anti-TNF antibodies have been used for treatment of IBD. About 20-25% of the patients with UC fail to respond to intensive and optimal medical therapy and therefore are referred to surgery for total proctocolectomy. In general, patients with CD are less responsive to medical therapy and usually do not respond to surgical treatment. Recently, anti-TNFxcex1 antibodies were introduced to treat patients with CD with reasonable efficacy, but this approach is ineffective in patients with UC. Thus, IBD is a medical problem that lacks an effective treatment.
The importance of management of gastrointestinal inflammation, particular chronic gastrointestinal inflammation, can not be underestimated, since the presence of gastrointestinal inflammation can be an early sign for risk of development of further serious conditions. For example, colorectal cancer represents the major cause for excess morbidity and mortality by malignant disease in ulcerative colitis as well as in Crohn""s disease. The risk for ulcerative colitis associated colorectal cancer is increased at least 2-fold compared to the normal population. Colorectal cancer is observed in 5.5-13.5% of all patients with ulcerative colitis and 0.4-0.8% of patients with Crohn""s disease. Ulcerative colitis associated colorectal cancer typically can occur in the entire colon, is often multifocal and of undifferentiated histology. Stage distribution and prognosis of ulcerative colitis associated colorectal cancer appears to be similar to that of sporadic colorectal cancer with an overall survival of about 40% (15-65%) after 5 years with tumor stage at diagnosis being the most important predictive parameter for survival (for a review see, e.g., Pohl et al. Hepatogastroenterology (2000) 47(31):57-70).
There is a need in the field for effective methods of treating gastrointestinal inflammation, particularly chronic gastrointestinal inflammation such as IBD. The present invention addresses this need.
The invention provides a method for ameliorating gastrointestinal inflammation, particularly chronic gastrointestinal inflammation such as inflammatory bowel disease (IBD), in a subject. In one embodiment, the method comprises administering an immunomodulatory nucleic acid to a subject suffering from or susceptible to gastrointestinal inflammation.
The immunomodulatory nucleic acid can be administered via gastroenteral or parenteral routes. Examples of gastroenteral routes include, but are not limited to, oral, gastric or rectal administration. Examples of parenteral routes include, but are not limited to, intradermal, intramuscular, subcutaneous or intravenous administration. The immunomodulatory nucleic acid can be administered alone or together with additional therapeutic agents.
In exemplary embodiments, the immunomodulatory nucleic acid comprises a non-coding oligonucleotide sequence that may include at least one unmethylated CpG motif. Examples of an immunomodulatory nucleic acid include, but are not limited to, sequences comprising 5xe2x80x2-rrcgyy-3xe2x80x2, such as AACGTT, AGCGTT, GACGTT, GGCGTT, AACGTC, and AGCGTC, 5xe2x80x2-rycgyy-3xe2x80x2 such as GTCGTT, 5xe2x80x2-rrcgyycg-3xe2x80x2, 5xe2x80x2-rycgyycg-3xe2x80x2 or 5xe2x80x2-(TCG)n-3xe2x80x2. An immunomodulatory nucleic acid of particular interest is one comprising the sequence 5xe2x80x2-AACGTTCG-3xe2x80x2. In one exemplary embodiment, the immunomodulatory nucleic acid is plasmid DNA or bacterial genomic DNA.